The heat-shock response, a fundamental defense mechanism against proteotoxic stress, is regulated by a family of heatshocktranscription factors (HSF). In humans HSF1 is considered the central regulator of heat-induced transcriptionalresponses. The main targets for HSF1 are specific promoter elements (HSE) located upstream of heat-shock genes encodingcytoprotective heat-shock proteins (HSP) with chaperone function. In addition to its cytoprotective function, HSF1 wasrecently hypothesized to play a more complex role, regulating the expression of non-HSP genes; however, the noncanonicalrole of HSF1 is still poorly understood. Herein we report that heat-stress promotes the expression ofcyclooxygenase-2 (COX-2), a key regulator of inflammation controlling prostanoid and thromboxane synthesis, resulting inthe production of high levels of prostaglandin-E2 in human cells. We show that heat-induced COX-2 expression is regulatedat the transcriptional level via HSF1-mediated signaling and identify, by in-vitro reporter gene activity assay and deletionmutantconstructs analysis, the COX-2 heat-responsive promoter region and a new distal cis-acting HSE located at position22495 from the transcription start site. As shown by ChIP analysis, HSF1 is recruited to the COX-2 promoter rapidly afterheat treatment; by using shRNA-mediated HSF1 suppression and HSE-deletion from the COX-2 promoter, we demonstratethat HSF1 plays a central role in the transcriptional control of COX-2 by heat. Finally, COX-2 transcription is also induced atfebrile temperatures in endothelial cells, suggesting that HSF1-dependent COX-2 expression could contribute to increasingblood prostaglandin levels during fever. The results identify COX-2 as a human non-classical heat-responsive gene, unveilinga new aspect of HSF1 function.

Regulation of Cyclooxygenase-2 Expression by Heat: A Novel Aspect of Heat Shock Factor 1 Function in Human Cells

Antonio Rossi;Edoardo Trotta;
2012

Abstract

The heat-shock response, a fundamental defense mechanism against proteotoxic stress, is regulated by a family of heatshocktranscription factors (HSF). In humans HSF1 is considered the central regulator of heat-induced transcriptionalresponses. The main targets for HSF1 are specific promoter elements (HSE) located upstream of heat-shock genes encodingcytoprotective heat-shock proteins (HSP) with chaperone function. In addition to its cytoprotective function, HSF1 wasrecently hypothesized to play a more complex role, regulating the expression of non-HSP genes; however, the noncanonicalrole of HSF1 is still poorly understood. Herein we report that heat-stress promotes the expression ofcyclooxygenase-2 (COX-2), a key regulator of inflammation controlling prostanoid and thromboxane synthesis, resulting inthe production of high levels of prostaglandin-E2 in human cells. We show that heat-induced COX-2 expression is regulatedat the transcriptional level via HSF1-mediated signaling and identify, by in-vitro reporter gene activity assay and deletionmutantconstructs analysis, the COX-2 heat-responsive promoter region and a new distal cis-acting HSE located at position22495 from the transcription start site. As shown by ChIP analysis, HSF1 is recruited to the COX-2 promoter rapidly afterheat treatment; by using shRNA-mediated HSF1 suppression and HSE-deletion from the COX-2 promoter, we demonstratethat HSF1 plays a central role in the transcriptional control of COX-2 by heat. Finally, COX-2 transcription is also induced atfebrile temperatures in endothelial cells, suggesting that HSF1-dependent COX-2 expression could contribute to increasingblood prostaglandin levels during fever. The results identify COX-2 as a human non-classical heat-responsive gene, unveilinga new aspect of HSF1 function.
2012
FARMACOLOGIA TRASLAZIONALE - IFT
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14243/77355
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